Dicer1 and miR-219 Are Required for Normal Oligodendrocyte Differentiation and Myelination

Jason C. Dugas; Trinna L. Cuellar; Anja Scholze; Brandon Ason; Adiljan Ibrahim; Ben Emery; Jennifer L. Zamanian; Lynette C. Foo; Michael T. McManus; Ben A. Barres

doi:10.1016/j.neuron.2010.01.027

Dicer1 and miR-219 Are Required for Normal Oligodendrocyte Differentiation and Myelination

Jason C. Dugas, Trinna L. Cuellar, Anja Scholze, Brandon Ason, Adiljan Ibrahim, Ben Emery, Jennifer L. Zamanian, Lynette C. Foo, Michael T. McManus, Ben A. Barres

Research output: Contribution to journal › Article › peer-review

469 Scopus citations

Abstract

To investigate the role of microRNAs in regulating oligodendrocyte (OL) differentiation and myelination, we utilized transgenic mice in which microRNA processing was disrupted in OL precursor cells (OPCs) and OLs by targeted deletion of Dicer1. We found that inhibition of OPC-OL miRNA processing disrupts normal CNS myelination and that OPCs lacking mature miRNAs fail to differentiate normally in vitro. We identified three miRNAs (miR-219, miR-138, and miR-338) that are induced 10-100× during OL differentiation; the most strongly induced of these, miR-219, is necessary and sufficient to promote OL differentiation, and partially rescues OL differentiation defects caused by total miRNA loss. miR-219 directly represses the expression of PDGFRα, Sox6, FoxJ3, and ZFP238 proteins, all of which normally help to promote OPC proliferation. Together, these findings show that miR-219 plays a critical role in coupling differentiation to proliferation arrest in the OL lineage, enabling the rapid transition from proliferating OPCs to myelinating OLs.

Original language	English (US)
Pages (from-to)	597-611
Number of pages	15
Journal	Neuron
Volume	65
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2010.01.027
State	Published - Mar 11 2010
Externally published	Yes

Keywords

DEVBIO
MOLNEURO

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2010.01.027

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@article{a37286f13dfa4860a25744d5ed458c57,

title = "Dicer1 and miR-219 Are Required for Normal Oligodendrocyte Differentiation and Myelination",

abstract = "To investigate the role of microRNAs in regulating oligodendrocyte (OL) differentiation and myelination, we utilized transgenic mice in which microRNA processing was disrupted in OL precursor cells (OPCs) and OLs by targeted deletion of Dicer1. We found that inhibition of OPC-OL miRNA processing disrupts normal CNS myelination and that OPCs lacking mature miRNAs fail to differentiate normally in vitro. We identified three miRNAs (miR-219, miR-138, and miR-338) that are induced 10-100× during OL differentiation; the most strongly induced of these, miR-219, is necessary and sufficient to promote OL differentiation, and partially rescues OL differentiation defects caused by total miRNA loss. miR-219 directly represses the expression of PDGFRα, Sox6, FoxJ3, and ZFP238 proteins, all of which normally help to promote OPC proliferation. Together, these findings show that miR-219 plays a critical role in coupling differentiation to proliferation arrest in the OL lineage, enabling the rapid transition from proliferating OPCs to myelinating OLs.",

keywords = "DEVBIO, MOLNEURO",

author = "Dugas, {Jason C.} and Cuellar, {Trinna L.} and Anja Scholze and Brandon Ason and Adiljan Ibrahim and Ben Emery and Zamanian, {Jennifer L.} and Foo, {Lynette C.} and McManus, {Michael T.} and Barres, {Ben A.}",

note = "Funding Information: We thank Prof. Klaus-Armin Nave for kindly providing the CNP-Cre mouse line, Prof. David Rowitch for providing the Olig2-Cre mouse line, and Prof. Chang-Zheng Chen for providing the floxed-Dicer mouse line. We would also like to thank Prof. Michael Wegner for generously providing the Sox6 antibody. This work was funded by the Myelin Repair Foundation and by NIH grant 5R03DA022201. ",

year = "2010",

month = mar,

day = "11",

doi = "10.1016/j.neuron.2010.01.027",

language = "English (US)",

volume = "65",

pages = "597--611",

journal = "Neuron",

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publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - Dicer1 and miR-219 Are Required for Normal Oligodendrocyte Differentiation and Myelination

AU - Dugas, Jason C.

AU - Cuellar, Trinna L.

AU - Scholze, Anja

AU - Ason, Brandon

AU - Ibrahim, Adiljan

AU - Emery, Ben

AU - Zamanian, Jennifer L.

AU - Foo, Lynette C.

AU - McManus, Michael T.

AU - Barres, Ben A.

N1 - Funding Information: We thank Prof. Klaus-Armin Nave for kindly providing the CNP-Cre mouse line, Prof. David Rowitch for providing the Olig2-Cre mouse line, and Prof. Chang-Zheng Chen for providing the floxed-Dicer mouse line. We would also like to thank Prof. Michael Wegner for generously providing the Sox6 antibody. This work was funded by the Myelin Repair Foundation and by NIH grant 5R03DA022201.

PY - 2010/3/11

Y1 - 2010/3/11

N2 - To investigate the role of microRNAs in regulating oligodendrocyte (OL) differentiation and myelination, we utilized transgenic mice in which microRNA processing was disrupted in OL precursor cells (OPCs) and OLs by targeted deletion of Dicer1. We found that inhibition of OPC-OL miRNA processing disrupts normal CNS myelination and that OPCs lacking mature miRNAs fail to differentiate normally in vitro. We identified three miRNAs (miR-219, miR-138, and miR-338) that are induced 10-100× during OL differentiation; the most strongly induced of these, miR-219, is necessary and sufficient to promote OL differentiation, and partially rescues OL differentiation defects caused by total miRNA loss. miR-219 directly represses the expression of PDGFRα, Sox6, FoxJ3, and ZFP238 proteins, all of which normally help to promote OPC proliferation. Together, these findings show that miR-219 plays a critical role in coupling differentiation to proliferation arrest in the OL lineage, enabling the rapid transition from proliferating OPCs to myelinating OLs.

AB - To investigate the role of microRNAs in regulating oligodendrocyte (OL) differentiation and myelination, we utilized transgenic mice in which microRNA processing was disrupted in OL precursor cells (OPCs) and OLs by targeted deletion of Dicer1. We found that inhibition of OPC-OL miRNA processing disrupts normal CNS myelination and that OPCs lacking mature miRNAs fail to differentiate normally in vitro. We identified three miRNAs (miR-219, miR-138, and miR-338) that are induced 10-100× during OL differentiation; the most strongly induced of these, miR-219, is necessary and sufficient to promote OL differentiation, and partially rescues OL differentiation defects caused by total miRNA loss. miR-219 directly represses the expression of PDGFRα, Sox6, FoxJ3, and ZFP238 proteins, all of which normally help to promote OPC proliferation. Together, these findings show that miR-219 plays a critical role in coupling differentiation to proliferation arrest in the OL lineage, enabling the rapid transition from proliferating OPCs to myelinating OLs.

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KW - MOLNEURO

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JO - Neuron

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Dicer1 and miR-219 Are Required for Normal Oligodendrocyte Differentiation and Myelination

Abstract

Keywords

ASJC Scopus subject areas

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